CN116808055A - 一种香紫苏内酯和两性霉素b联合抗新型隐球菌的方法 - Google Patents
一种香紫苏内酯和两性霉素b联合抗新型隐球菌的方法 Download PDFInfo
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Abstract
本发明为一种香紫苏内酯和两性霉素B联合抗新型隐球菌的方法，公开了一种与两性霉素B联用的芳香植物提取物，所述芳香植物提取物以香紫苏内酯为活性成分，为香紫苏内酯开辟了一种新用途，作为抗真菌药物的增效剂，可降低抗真菌药物的用药剂量，从而减轻了药物的毒副作用，特别是两性霉素B，能够有效减少两性霉素B的最小抑菌浓度（MIC）；显著提高两性霉素B的抗真菌效果，从而减少治疗过程中两性霉素B的用量，进而减少其毒副作用。
Description
技术领域
本发明涉及抗真菌治疗领域，是香紫苏内酯与两性霉素B组合物在制备抗真菌药物中的应用。
背景技术
真菌病原体对全球人类健康、粮食安全和生物多样性具有深远影响。机会性真菌病原体已成为人类死亡的主要原因，特别是在有潜在健康状况或正在接受免疫抑制治疗的个体中，每年的死亡率约为150万。主要病原体包括念珠菌、曲霉和隐球菌。新型隐球菌（Cryptococcus neoformans）是继白色念珠菌之后最常见的条件致病真菌，在免疫功能低下或缺陷时，可发生全身播散感染，特别是侵袭中枢神经系统导致隐球菌性脑膜炎（CNS）。隐球菌性脑膜炎（简称“隐脑”）的死亡率在发达国家达到10%～30%，在医疗体系不完善的发展中国家可达到50%～100%。特别是获得性免疫缺陷综合征（AIDS）的流行，使得隐脑的发病率显著增加。在撒哈拉以南地区，隐脑已经超越肺炎链球菌和脑膜炎球菌性脑膜炎，成为最主要的社区获得性脑膜炎。
微生物具有对抗菌药物产生耐药性的显著能力，威胁到有限抗菌药物库的功效，并成为严重的公共卫生危机。这对于真菌病原体尤其令人担忧，因为真菌病原体会导致毁灭性的侵袭性感染，治疗方案除5-氟胞嘧啶（5FC）外，目前临床应用的抗真菌药物只有三类，即唑类、多烯类和棘白菌素类，因此，真菌病原体对这些药物出现耐药性使真菌疾病成为全球人类健康问题。
发现抗真菌药物的一个主要障碍是确定真菌中缺乏宿主毒性的分子能够特异性参与的重要靶点。拓展药物靶向空间的一个有希望的策略是探索联合治疗。这种方法是治疗艾滋病、疟疾和结核病的基础，具有多种优势，包括降低耐药率、提高效力、降低宿主毒性和扩大治疗范围。药物组合也可用于靶向耐药机制本身，特别是涉及耐药性的机制。
Robbins等人筛选了六种亚抑制浓度的抗真菌药物，结合约3600个小分子，对抗四种真菌。这项研究确定了几种小分子，包括FDA批准的药物，它们可以提高抗真菌药物的疗效，甚至增强耐药菌株中抗真菌药物的活性。也可以直接使用耐药菌株进行组合筛选，以识别可用于治疗耐药生物体的化合物，并减少交叉耐药分子的识别。使用耐棘白菌素的白色念珠菌进行的筛选表明，金属螯合剂DTPA是卡泊芬净活性的增强剂，与单独使用每种药物相比，DPTA和卡泊芬净联合治疗显著提高了接种耐棘白菌素的小鼠的存活率。
高成本和严重的副作用限制了抗真菌药物的组合。此外，各种抗真菌组合的协同或拮抗作用的矛盾结果也有报道。因此，研究的重点已转移到检查典型抗真菌药物和非抗真菌药物的组合。
两性霉素B(Amphotericin B, AmB)是一种多烯类抗真菌药物，具有很强的抗真菌活性，目前两性霉素B仍是许多危及生命的深部真菌感染治疗的首选药物，由于其抗真菌谱广，疗效确切，半衰期长，被誉为治疗深部真菌感染的“黄金标准”，但两性霉素B存在在缺陷是不容忽视的，它的毒性较大、不良反应较多，普通注射剂给药的患者常出现严重的肾毒性、肝脏毒性和溶血毒性，并伴随寒战、发冷、恶心和呕吐等症状。这些严重的副作用，严重限制了两性霉素B在临床上的使用范围。
香紫苏内酯作为香紫苏醇进一步化学修饰后的产物，除了用于天然龙涎香代用品的合成和香精的调配，其本身也具有很好的生物活性。2019年Khruengsai S 等研究表明，香紫苏内酯是一种重要的抑菌化合物，对里氏木霉和可可毛色二孢菌具有一定的抗真菌作用，可作为植物病害的天然杀菌剂，并用于多种农业植物病原菌的生防。2020年EdouarzinEdruce 等研究表明，drimane倍半萜是一种广谱抗真菌化合物，香紫苏内酯作为drimane倍半萜化合物的一种，可有效杀灭白色念珠菌、隐球菌、曲霉菌、子囊菌、肺孢子菌等多种人类病原真菌，需要特别注意该萜类化合物也可以有效清除对氟康唑等唑类抗真菌药耐药性真菌，如白色念珠菌、光滑念珠菌、克鲁斯念珠菌、近平滑念珠菌、耳念珠菌等。在白色念珠菌感染的线虫模型中，drimane可将蠕虫中白色念珠有效清除并具有良好的耐受性。2020年Qing Chen等研究表明香紫苏内酯是一种针对病毒融合过程的EBOV进入抑制剂，确定了香紫苏内酯对丝状病毒具有新的生物活性。
综上，虽然香紫苏内酯具有良好的生物活性，但至今未见香紫苏内酯与多烯类抗真菌药物作为抗真菌药物组合物的报道，因此，开发新的抗真菌药物组合物具有很好的现实意义。
发明内容
本发明的目的一方面在于提供一种香紫苏内酯作为抗真菌药物组合物的新用途。
本发明的目的另一方面在于提供一种抗真菌的组合物，旨在解决现有技术中存在的抗真菌药物组合匮乏、抗真菌药物毒副作用大的问题。
本发明提供了一种两性霉素B增效剂，所述增效剂以香紫苏内酯为活性成分，还可以包括药学上可接受的载体。
本发明提供了一种抗真菌组合物，所述组合物包含两性霉素B和香紫苏内酯。
优选的，所述组合物中香紫苏内酯和两性霉素B的质量比为(0.195-100):(0.125-0.5)；优选的，香紫苏内酯和两性霉素B的质量比为(0.195-0.781):0.25；更优选的，香紫苏内酯和两性霉素B的质量比为(0.391-0.781):0.125。
本发明还提供了上述组合物在制备抗真菌药物中的用途。
优选的，所述抗真菌药物是抗新型隐球菌(Cryptococcus neoformans ATCC32719)药物。
此外，本发明所述的抗真菌药物组合物还可以包含药学上可接受的载体。
相比于现有技术的缺点和不足，本发明的有益效果是：
本发明公开了一种香紫苏内酯和两性霉素B组合物协同抗真菌的方法，为香紫苏内酯开辟了一种新用途，作为抗真菌药物的增效剂，能够有效减少两性霉素B的最小抑菌浓度（MIC）；显著提高两性霉素B的抗真菌效果，从而减少治疗过程中两性霉素B的用量，进而减少其毒副作用。
具体实施方式
为了使发明的目的、技术方案及优点更加清晰明白，下面通过实施例来具体说明本发明的内容。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
应当明确的是，下述实施例中所使用的实验方法如无特殊说明，均为常规方法，下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
香紫苏内酯购自上海源叶生物科技有限公司（产品货号：B21373）。
新型隐球菌Cryptococcus neoformans ATCC 32719 购自北京北纳创联生物技术研究院。
两性霉素B购自上海阿拉丁生化科技股份有限公司（产品货号：A105482）。
实施例1 香紫苏内酯和两性霉素B联用抗真菌活性测试。
应用棋盘稀释法对香紫苏内酯和两性霉素B联用抗真菌（新型隐球菌Cryptococcus neoformans ATCC 32719）活性进行测试。
1、将新型隐球菌接种在YM平板上，26℃，湿度为 80％的条件下孵育72小时。
2、将香紫苏内酯和两性霉素B分别溶于DMSO中，至浓度分别为20mg/ml与0.8mg/ml，保存于-80℃冰箱备用。
3、测定最低抑菌浓度（MIC）
(1)参照国际临床和实验室标准化协会（Clinical and Laboratory StandardsInstitute 简称：CLSI）M27-A3版，即“酵母菌肉汤稀释法抗真菌药敏实验方案”。采用方案中推荐的液体培养基（RPMI 1640）将贮存的20mg/ml的香紫苏内酯和0.8mg/ml的两性霉素B溶液配置成一系列稀释浓度的的香紫苏内酯和两性霉素B药液。
(2)将新型隐球菌（Cryptococcus neoformans ATCC 32719）接种到96孔板中，每孔100μL（约2×104个细胞），分别加入50μL香紫苏内酯和两性霉素B药液，药液的组合方式如下：
第一个药物两性霉素B在96孔板上按稀释浓度从上到下纵向排布（每一横排的所有测试孔两性霉素B浓度相同），每孔50μL；第二个药物香紫苏内酯按稀释浓度从左到右横向排布（每一列所有测试孔的香紫苏内酯浓度相同），每孔50μL。记录每一个测试组两性霉素B和香紫苏内酯的浓度，同时设置单独加入含不同浓度香紫苏内酯和两性霉素B药液的测试孔，每孔加入100μL，以及设置不加任何药物的空白对照组，做三个平行的96孔板，结果取平均值。
（3）将96孔板于37℃孵育72小时。
（4）MIC值定义为视觉观察测试孔清晰，未见有真菌生长的最低药物浓度。
此处设如下定义：通过抑制浓度系数FICI来判断两个药物A和B之间是协同、相加
还是拮抗作用。
其中，FICI＝(MIC药物组合中的A / MICA单独A)+(MIC药物组合中的B / MICB单独B)，如果FICI值≤0.5，则表明药物A和B之间存在协同作用；若FICI值在0 .5～4 .0之间，则表明药物A和B的活性相加；若FICI值＞4 .0，则表明药物A和B之间存在拮抗作用。
通过以上定义检测香紫苏内酯和两性霉素B的相互作用，由于香紫苏内酯本身抗新型隐球菌活性较差，其(MIC药物组合中的香紫苏内酯/ MIC香紫苏内酯）可忽略不计，结果如表1所示。
表1香紫苏内酯和两性霉素B组合后的FICI
由上表可知，两性霉素B终浓度为0.25μg/mL、香紫苏内酯终浓度为0.195μg/mL；两性霉素B终浓度为0.25μg/mL、香紫苏内酯终浓度为0.391μg/mL；两性霉素B终浓度为0.25μg/mL、香紫苏内酯终浓度为0.781μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为0.391μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为0.781μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为1.563μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为3.125μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为6.25μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为12.5μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为25μg/mL；两性霉素B终浓度为0.125μg/mL、香紫苏内酯终浓度为50μg/mL，共计十一组药物组合中，两性霉素B和香紫苏内酯存在协同抗真菌作用。其中随着香紫苏内酯浓度的升高，两性霉素B和香紫苏内酯的协同抗新型隐球菌的活性不断增强。
本发明药物组合物所能抑制的真菌来源广泛，包括但不限于对机体危害较轻的浅部真菌和危害严重的深部真菌，药物组合物对真菌的最佳抑制效果还可通过上述实施方法确定两者之间的最佳混合比例来获得。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (4)
1.一种组合物在制备抗真菌药物中的用途，所述组合物包含两性霉素B和香紫苏内酯，所述真菌为新型隐球菌(Cryptococcus neoformans ATCC 32719)。
2.根据权利要求1所述的组合物，其特征在于，所述两性霉素B、香紫苏内酯的质量比范围为（0.125-0.5）：（0.195-100）。
3.一种组合物在抗真菌中的应用，其特征在于，所述组合物包含两性霉素B和香紫苏内酯，所述真菌为新型隐球菌ATCC 32719，所述组合物中两性霉素B和香紫苏内酯的质量比0.25：（0.195-0.781）。
4.一种组合物在抗真菌中的应用，其特征在于，所述组合物包含两性霉素B和香紫苏内酯，所述真菌为新型隐球菌ATCC 32719，所述组合物中两性霉素B和香紫苏内酯的质量比0.125：（0.391-50）。
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